Abstract Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder characterized by chorea, cognitive deficits and psychiatric disturbances. The main neuropathology is the loss of medium-sized spiny neurons (MSNs) in the striatum, but cell loss also occurs in cerebral cortex, hypothalamus, as well as other brain regions. Neuronal loss is preceded by reductions in white matter volume, suggesting myelin breakdown and altered synaptic connectivity. Using electrophysiological methods, we previously demonstrated significant alterations in synaptic activity, in particular a progressive disconnectio between cortex and striatum, and an increase in striatal inhibitory activity, both of which markedly alter signaling to output regions of the basal ganglia and contribute to motor symptoms. HD treatments have primarily focused on preventing neurodegenerative changes in the striatum. However, an effective therapy has to consider global changes as the mutation is widely expressed in multiple brain areas and peripheral organs. It is becoming increasingly recognized that one of the main features of HD is a metabolic disturbance that accompanies neurological symptoms. Impaired glucose metabolism and inadequate energy supply can lead to cell stress and eventual degeneration. In addition, a disruption in the brain cholesterol biosynthetic pathway occurs early, which could partially explain synaptic dysfunction and myelin breakdown. The experiments in this application are designed to examine the role of alterations in lipid metabolism, in particular brain cholesterol, as a primary etiologic factor in motor and synaptic disturbances in genetic mouse models of HD and to rescue these alterations by manipulating cholesterol levels. In Aim 1, we will examine the effects of a Ketogenic Diet (a diet rich in fat, low in carbohydrates and normal in protein levels) on behavior and electrophysiology of MSNs. This diet is effective in other neurological disorders and in HD it could provide essential alternative sources of energy to alleviate symptoms. In Aim 2 we will examine potential mechanisms by modulating cholesterol levels in slices. Using this global strategy, we hope to provide a novel method to rescue the synaptic and behavioral phenotype. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder characterized by uncontrollable movements and cognitive deficits. One of the main features of HD is a metabolic disturbance leading to cell stress and eventual degeneration. The experiments in this application examine the role of lipid metabolism as a causative agent of motor and synaptic alterations in mouse models and to rescue these changes by manipulating lipid metabolism, in particular brain cholesterol levels.